One-Pot Synthesis of 1-Hydroxy-1,1-bis(phosphonic acid)s
= 20 ppm. HRMS (ESI): calcd. for C8H12O7P2 [M + Na]+
304.9962; found 304.9955.
carboxylic acid 10, catecholborane (2.1 equiv.), and P(OSiMe3)3
(3.1 equiv.), the expected 1-hydroxy-1,1-bis(phosphonic acid) was
purified by dissolving the residue in a minimum amount of meth-
anol followed by dilution with Et2O. Product 26 was isolated as a
2-(Adamant-1-yl)-1-hydroxyethylidene-1,1-bis(phosphonic acid) (22):
According to the general procedure for 17 and starting with carb-
oxylic acid 6, the expected 1-hydroxy-1,1-bis(phosphonic acid) was
purified by dissolving the residue in a minimum amountb of dichlo-
romethane followed by dilution with Et2O. Compound 22 was iso-
1
white powder (50% yield). H NMR (300 MHz, D2O): δ = 3.58 [t,
3JH,P = 12 Hz, 2 H, CH2C(OH)(PO3H2)2], 2.99 [s, 6 H, N(CH3)2]
1
ppm. 13C{1H} NMR (75 MHz, D2O): δ = 71.32 (t, JC,P
=
135.7 Hz), 60.97, 46.20 ppm. 31P{1H} NMR (121.5 MHz, D2O): δ
= 14.25 ppm. HRMS (ESI): calcd. for C4H13NO7P2 [M – H]–
248.0094; found 248.0067.
1
lated as a colorless oil (62% yield). H NMR (300 MHz, CD3OD/
CDCl3): δ = 1.92 [t, 3JH,P = 15 Hz, 2 H, CH2C(OH)(PO3H2)2], 1.89
(br. s, 3 H, CH), 1.82 (br. s, 6 H, CH2), 1.65 (br. s, 6 H, CH2) ppm.
1
13C{1H} NMR (75 MHz, CD3OD/CDCl3): δ = 75.17 (t, JC,P
=
1-Hydroxy-3-[(methyl)(3-phenoxypropyl)amino]propylidene-1,1-bis-
(phosphonic acid) (27): According to the general procedure for 17
3
139 Hz), 45.62, 44.00, 37.83, 35.25 (t, JC,P = 10 Hz), 29.98 ppm.
31P{1H} NMR (121.5 MHz, CD3OD/CDCl3): δ = 20 ppm. HRMS and starting with carboxylic acid 11, catecholborane (2.1 equiv.),
(ESI): calcd. for C12H22O7P2 [M + Na]+ 363.0744; found 363.0739.
and P(OSiMe3)3 (3.1 equiv.), the expected 1-hydroxy-1,1-bis(phos-
phonic acid) was purified by dissolving the residue in a minimum
amount of methanol followed by dilution with Et2O. Product 27
1-Hydroxy-2-[4-(2-methylpropyl)phenyl]propylidene-1,1-bis(phos-
phonic acid) (23): According to the general procedure for 17 and
starting with carboxylic acid 7, the expected 1-hydroxy-1,1-bis(phos-
phonic acid) was purified by dissolving the residue in a minimum
amount of methanol followed by dilution with Et2O. Compound
23 was isolated as a colorless oil (62% yield) and purified by low-
pressure reverse-phase chromatography (C18, from 3% MeOH in
1
was isolated as a white hygroscopic powder (85% yield). H NMR
(300 MHz, [D6]DMSO): δ = 7.23 (t, J = 7 Hz, 2 H, HAr), 6.97–
6.80 (m, 3 H, HAr), 3.99 (t, J = 6 Hz, 2 H, OCH2), 3.55–3.00 [m,
4 H, CH2N(Me)CH2], 2.74 (s, 3 H, NCH3), 2.23 [m, 2 H,
CH2C(OH)(PO3H2)2], 2.06 (m, 2 H, OCH2CH2CH2) ppm. 13C{1H}
NMR (75 MHz, [D6]DMSO): δ = 158.87, 130.16, 121.64, 115.18,
1
water to 100% MeOH). H NMR (300 MHz, D2O): δ = 7.19 (d, J
1
72.33 (t, JC,P = 136 Hz), 65.51, 54.31, 53.37, 40.37, 28.28,
= 7 Hz, 2 H, HAr), 6.85 (d, J = 7 Hz, 2 H, HAr), 3.39 [m, 1 H,
CH3CHC(OH)(PO3H2)2], 2.13 (br. s, 2 H, CH2), 1.54 [m, 1 H,
(CH3)2CH], 1.41 [d, J = 7 Hz, 3 H, CH3CHC(OH)(PO3H2)2], 0.57
[d, J = 8 Hz, 6 H, (CH3)2CH] ppm. 13C{1H} NMR (75 MHz,
D2O): δ = 140.02, 138.25 (t, 3JC,P = 9 Hz), 129.76, 128.33, 76.53 (t,
24.44 ppm. 31P{1H} NMR (121.5 MHz, [D6]DMSO): δ = 19 ppm.
HRMS (ESI): calcd. for C13H23NO8P2 [M + H]+ 384.0983; found
384.0979.
1-Hydroxy-3-(methylamino)propylidene-1,1-bis(phosphonic acid)
(28): According to the general procedure for 17 and starting with
carboxylic acid 12, catecholborane (2.1 equiv.), and P(OSiMe3)3
1JC,P = 142 Hz), 44.52, 43.27, 29.72, 21.89 (2 C), 17.09 ppm.
2
31P{1H} NMR (121.5 MHz, D2O): δ = 19.77 (AB system, JP,PЈ
=
2
33 Hz, 1 P), 18.64 (AB system, JP,PЈ = 33 Hz, 1 P) ppm. HRMS (3.1 equiv.), the expected 1-hydroxy-1,1-bis(phosphonic acid) was
(ESI): calcd. for C13H22O7P2 [M – H]– 351.0770; found 351.0762.
purified by dissolving the residue in a minimum amountb of meth-
anol followed by dilution with Et2O. Product 28 was isolated as a
white hygroscopic powder (73% yield). 1H NMR (300 MHz, D2O):
3-{[(5-Dimethylamino)naphthyl-1-sulfonyl](methyl)amino}-1-
hydroxypropylidene-1,1-bis(phosphonic acid) (24): According to the
general procedure for 17 and starting with carboxylic acid 8, cat-
echolborane (3.1 equiv.), and P(OSiMe3)3 (4.1 mol equiv.), the ex-
pected 1-hydroxy-1,1-bis(phosphonic acid) was purified by dissolv-
ing the residue in a minimum amount of methanol followed by
dilution with Et2O. Compound 24 was isolated as a white hygro-
3
δ = 3.35 (t, J = 7 Hz, 2 H, NH2CH2), 2.69 (br. s, 3 H, CH3), 2.31
3
[sept, J = 7 Hz, 2 H, CH2C(OH)(PO3H2)2] ppm. 13C{1H} NMR
1
(75 MHz, D2O): δ = 70.33 (t, JC,P = 141 Hz), 43.78 (t, JC,P
=
7 Hz), 31.07, 27.56 ppm. 31P{1H} NMR (1216.5 MHz, D2O): δ =
18 ppm.
1
scopic fluorescent powder (86% yield). H NMR (300 MHz, D2O/
2-Amino-1-hydroxyethylidene-1,1-bis(phosphonic acid) (29): Accord-
NaOD): δ = 8.37 (d, J = 6 Hz, 1 H, HAr), 8.17 (d, J = 6 Hz, 1 H, ing to the general procedure for 17 and starting with carboxylic
HAr), 8.05 (d, J = 6 Hz, 1 H, HAr), 7.67–7.50 (m, 2 H, HAr), 7.30 acid 13, catecholborane (3.1 equiv.), and P(OSiMe3)3 (4.1 equiv.),
(d, J = 6 Hz, 1 H, HAr), 3.62 [m, 2 H, SO2N(CH3)CH2], 2.79 [s, 3
H, SO2 N(CH3 )], 2.74 [s, 6 H, N(CH3 )2 ], 2.19 [m, 2 H,
the expected 1-hydroxy-1,1-bis(phosphonic acid) was purified by
dissolving the residue in a minimum amount of methanol followed
CH2CH2C(OH)(PO3H2)2] ppm. 13C{1H} NMR (75 MHz D2O/ by dilution with Et2O. Product 29 was isolated as a white hygro-
NaOD): δ = 149.31, 132.09, 128.71, 128.17, 127.98, 127.83, 127.49,
scopic powder (80% yield). 1H NMR (300 MHz, D2O): δ = 2.84
1
3
122.88, 118.41, 114.77, 74.14 (t, JC,P = 134 Hz), 45.96 (t, JC,P
=
[t, JH,P = 12 Hz, 2 H, NH2CH2C(OH)(PO3H2)2] ppm. 13C{1H}
7 Hz), 43.68 (2 C), 33.36, 32.97 ppm. 31P{1H} NMR (121.5 MHz, NMR (75 MHz, D2O): δ = 75.95 (t, JC,P = 133 Hz), 46.02 ppm.
1
D2O/NaOD): δ = 18 ppm. HRMS (ESI): calcd. for C16H24N2O9P2S
31P{1H} NMR (121.5 MHz, D2O): δ = 18 ppm.
[M – H]– 481.0605; found 481.0600.
4-Amino-1-hydroxybutylidene-1,1-bis(phosphonic acid) (Alendron-
ate, 30): According to the general procedure for 17 and starting
with carboxylic acid 14, catecholborane (3.1 equiv.), and P(O-
SiMe3)3 (4.1 equiv.), the expected 1-hydroxy-1,1-bis(phosphonic
acid) was purified by dissolving the residue in a minimum amount
of methanol followed by dilution with Et2O. Product 30 was iso-
2-[(Benzyloxycarbonyl)amino]ethylidene-1-hydroxy-1,1-bis(phos-
phonic acid) (25): According to the general procedure for 17 and
starting with carboxylic acid 9, catecholborane (2.1 equiv.), and
P(OSiMe3)3 (3.1 equiv.), product 25 was isolated as a colorless oil
1
(75% yield). H NMR (300 MHz, [D6]DMSO): δ = 7.42–7.25 (m,
5 H, HAr), 5.01 (s, 2 H, OCH2Ph), 3.55 [t, JH,P = 12 Hz, 2 H, lated as a white hygroscopic powder (51 % yield). 1H NMR
3
NHCH2C(OH)(PO3H2)2] ppm. 13C{1H} NMR (75 MHz, [D6]-
(300 MHz, D2O): δ = 3.03 (m, 2 H, NH2CH2), 2.20–1.70 [m, 4 H,
DMSO): δ = 156.15, 137.11, 128.40, 127.80, 127.76, 71.32 (t, JC,P
CH2CH2C(OH)(PO3H2)2] ppm. 13C{1H} NMR (75 MHz, D2O): δ
1
= 143 Hz), 65.48, 44.09 ppm. 31P{1H} NMR (121.5 MHz, = 73.09 (t, 1JC,P = 139 Hz), 39.85, 30.48, 21.96 ppm. 31P{1H} NMR
[D6]DMSO): δ = 17 ppm. HRMS (ESI): calcd. for C10H15NO9P2
(121.5 MHz, D2O): δ = 18 ppm.
[M + Na]+ 378.0125; found 378.0120.
1,2-Dihydroxy-2-phenylethylidene-1,1-bis(phosphonic acid) (31): Ac-
2-(Dimethylamino)-1-hydroxyethylidene-1,1-bis(phosphonic acid) cording to the general procedure for 17 and starting with racemic
(26): According to the general procedure for 17 and starting with 15, catecholborane (2.1 equiv.), and P(OSiMe3)3 (3.1 equiv.), the ex-
Eur. J. Org. Chem. 2011, 7148–7154
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7153